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Keywords: 20-hydroxyeicosatetraenoic acid (20-HETE)
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Articles
Journal:
Clinical Science
Clin Sci (Lond) (2013) 124 (12): 695–700.
Published: 26 February 2013
... cerebral circulation cytochrome P450-4A (CYP4A) 20-hydroxyeicosatetraenoic acid (20-HETE) oxidative stress salt-sensitive vascular function 20-HETE (20-hydroxyeicosatetraenoic acid), a vasoconstrictor metabolite of arachidonic acid generated by CYP4A (cytochrome P450 4A) enzymes, plays a vital...
Abstract
20-HETE (20-hydroxyeicosatetraenoic acid), a vasoconstrictor metabolite of arachidonic acid formed through the action of CYP4A (cytochrome P450-4A) in vascular smooth muscle cells, has been implicated in the development of hypertension and vascular dysfunction. There have been a number of reports in human subjects demonstrating an association between elevated urinary excretion of 20-HETE and hypertension, as well as increased 20-HETE production and vascular dysfunction. The Dahl SS (salt-sensitive) rat is a genetic model of salt-sensitive hypertension that exhibits vascular dysfunction, even when maintained on a normal-salt diet and before the development of hypertension. This mini-review highlights our current research on the role of CYP4A and 20-HETE in the vascular dysfunction of the Dahl SS rat. In our studies, the SS rat is compared with the consomic SS-5 BN rat, having chromosome 5 from the salt-resistant Brown Norway rat (carrying all CYP4A genes) introgressed on to the SS genetic background. Our laboratory has demonstrated restoration of normal vascular function in the SS rat with inhibition of the CYP4A/20-HETE pathway, suggesting a direct role for this pathway in the vascular dysfunction in this animal model. Our studies have also shown that the SS rat has an up-regulated CYP4A/20-HETE pathway within their cerebral vasculature compared with the SS-5 BN consomic rat, which causes endothelial dysfunction through the production of ROS (reactive oxygen species). Our data shows that ROS influences the expression of the CYP4A/20-HETE pathway in the SS rat in a feed-forward mechanism whereby elevated ROS stimulates production of 20-HETE. The presence of this vicious cycle offers a possible explanation for the spiralling effects of elevated 20-HETE on the development of vascular dysfunction in this animal model.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2013) 124 (5): 333–342.
Published: 16 November 2012
... ). 17 5 2012 27 8 2012 3 9 2012 3 9 2012 © The Authors Journal compilation © 2013 Biochemical Society 2013 20-hydroxyeicosatetraenoic acid (20-HETE) cytochrome P450 4A ω-hydroxylase (CYP4A) oxidative stress salt-sensitive hypertension vascular dysfunction...
Abstract
The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 ω-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5 BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5 BN rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5 BN rats was present in SS-5 BN rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS ( N -methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20-hydroxyeicosa-6( Z ),15( Z )-dienoic acid]. The restored response to ACh in DDMS-treated SS rats was inhibited by L -NAME ( N G nitro- L -arginine methyl ester) and unaffected by indomethacin or MS-PPOH [ N -methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide]. Vascular relaxation responses to the NO donor C 5 FeN 6 Na 2 O were intact in both SS and SS-5 BN rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5 BN rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction.
Articles
Natalie C. Ward, Kevin D. Croft, David Blacker, Graeme J. Hankey, Anne Barden, Trevor A. Mori, Ian B. Puddey, Christopher D. Beer
Journal:
Clinical Science
Clin Sci (Lond) (2011) 121 (11): 501–507.
Published: 09 August 2011
...) epoxyeicosatrienoic acid (EET) 20-hydroxyeicosatetraenoic acid (20-HETE) oxidative stress Ischaemic brain injury is thought to result from a cascade of events that includes inflammation, free radical formation and cell death [ 1 ]. Studies have shown significant increases in brain concentrations of NEFA...
Abstract
CYP450AAM [arachidonic acid metabolites of the CYP450 (cytochrome P450) enzyme system] have a range of biological functions. CYP450AAM are involved in the pathogenesis of hypertension, renal function and vascular function, yet their role in stroke has not been clarified. We aimed at determining the levels of circulating CYP450 metabolites in patients with acute ischaemic stroke (<96 h) compared with healthy age- and gender-matched controls. This was a retrospective case-controlled study of 44 acute ischaemic stroke patients and 44 matched controls. A subset of acute ischaemic stroke patients was available for follow-up. Acute ischaemic stroke patients had elevated plasma CYP450AAM, including 20-HETE (20-hydroxyeicosatetraenoic acid) (1921±170 compared with 1108±170 pmol/l, P <0.001), EETs (epoxyeicosatrienoic acids) (77.88±3.34 compared with 35.35±3.34 nmol/l, P <0.0001) and DiHETEs (dihydroxyeicosatetraenoic acids) (92.87±4.61 compared with 68.17±4.61 nmol/l, P <0.0001), as well as increased plasma F 2 -isoprostane levels (3754±538 compared with 1947±538 pmol/l, P <0.02), the latter a marker of oxidative stress, compared with controls. In a subset analysis of the stroke patients, plasma 20-HETE, EETs and F 2 -isoprostanes were attenuated 30 days after the stroke. Baseline 20-HETE levels were also associated with lesion size and functional indices within the stroke patients. The present study highlights the elevation in CYP450AAM and oxidative stress in acute ischaemic stroke patients. Further investigation of the effect this has on long-term clinical outcome or whether this can be modified by treatment is warranted.